Skip to main content
SpringerLink
Log in

Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Inflammatory processes have been implicated in the cascade of events that lead to nerve cell death. In the nervous system, a number of genes involved in inflammation pathways are regulated post-transcriptionally via the interaction of their mRNAs with specific RNA-binding Hu proteins, the vertebrate homologues of the Drosophila ELAV (for embryonic lethal abnormal vision). The gene encoding ELAVL4, a member of the Hu family of proteins, is located 2 Mb from the chromosome 1p linkage region peak for age-at-onset (AAO) of Parkinson disease (PD) (LOD=3.41). Nine single-nucleotide polymorphisms (SNPs) in ELAVL4 were genotyped for 266 multiplex families (1,223 samples). Additional genotyping in 377 singleton families was performed for a subset of five SNPs (SNPs 1–5) that were not in linkage disequilibrium. SNP 2 (located in the first intron of ELAVL4) showed a strong significant association with AAO of PD (P=0.006), and SNP 5 (a coding SNP in ELAVL4) showed a moderately significant association (P=0.035). Haplotype analysis revealed that the A-C haplotype at SNPs 2 and 3 has the strongest significant association with AAO (P=0.0001) among all combinations of two or three loci. The A-C haplotype remained significant for AAO after the inclusion of the C allele at SNP 5 to this haplotype (A-C-C haplotype, P=0.00018). Although SNP 5 was found to associate with PD risk in the early-onset subset of PD families (at least one affected with AAO <40 years, 60 families), we believe that it is a by-product of its association with AAO. Taken together, these results suggest a potential role for ELAVL4 as a modifier gene for AAO of PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abecasis GR, Cookson WO (2000) GOLD—graphical overview of linkage disequilibrium. BioInformatics 16:182–183

    Article  CAS  PubMed  Google Scholar 

  • Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292

    Article  CAS  PubMed  Google Scholar 

  • Akamatsu W, Okano HJ, Osumi N, Inoue T, Nakamura S, Sakakibara S, Miura M, Matsuo N, Darnell RB, Okano H (1999) Mammalian ELAV-like neuronal RNA-binding proteins HuB and HuC promote neuronal development in both the central and the peripheral nervous systems. Proc Natl Acad Sci USA 96:9885–9890

    Google Scholar 

  • Antic D, Keene JD (1997a) Embryonic lethal abnormal visual RNA-binding proteins involved in growth, differentiation, and posttranscriptional gene expression. Am J Hum Genet 61:273–278

    Google Scholar 

  • Antic D, Keene JD (1997b) Embryonic lethal abnormal visual RNA-binding proteins involved in growth, differentiation, and posttranscriptional gene expression. Am J Hum Genet 61:273–278

    Google Scholar 

  • Aranda-Abreu GE, Behar L, Chung S, Furneaux H, Ginzburg I (1999) Embryonic lethal abnormal vision-like RNA-binding proteins regulate neurite outgrowth and tau expression in PC12 cells. J Neurosci 19:6907–6917

    Google Scholar 

  • Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, Nemachek C, Green SR, Przedborski S, Gendelman HE (2004) Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 101:9435–9440

    Google Scholar 

  • Benyahia B, Liblau R, Merle-Beral H, Tourani JM, Dalmau J, Delattre JY (1999) Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies. Ann Neurol 45:162–167

    Google Scholar 

  • Brennan CM, Steitz JA (2001) HuR and mRNA stability. Cell Mol Life Sci 58:266–277

    Google Scholar 

  • Campos AR, Grossman D, White K (1985) Mutant alleles at the locus elav in Drosophila melanogaster lead to nervous system defects: a developmental-genetic analysis. J Neurogenet 2:197–218

    Google Scholar 

  • Cok SJ, Acton SJ, Morrison AR (2003) The proximal region of the 3′-untranslated region of cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR, TIA-1, TIAR, and the heterogeneous nuclear ribonucleoprotein U. J Biol Chem 278:36157–36162

    Google Scholar 

  • Cuadrado A, Navarro-Yubero C, Furneaux H, Kinter J, Sonderegger P, Munoz A (2002) HuD binds to three AU-rich sequences in the 3′-UTR of neuroserpin mRNA and promotes the accumulation of neuroserpin mRNA and protein. Nucleic Acids Res 30:2202–2211

    Google Scholar 

  • Dalmau JO, Posner JB (1999) Paraneoplastic syndromes. Arch Neurol 56:405–408

    Google Scholar 

  • Gao HM, Liu B, Zhang W, Hong JS (2003) Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci 24:395–401

    Google Scholar 

  • Good PJ (1995) A conserved family of elav-like genes in vertebrates. Proc Natl Acad Sci USA 92:4557–4561

    Google Scholar 

  • Griffin WS and Mrak RE (2002) Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J Leukoc Biol 72:233–238

    Google Scholar 

  • Grimaldi LM, Casadei VM, Ferri C, Veglia F, Licastro F, Annoni G, Biunno I, De Bellis G, Sorbi S, Mariani C, Canal N, Griffin WS, Franceschi M (2000) Association of early-onset Alzheimer’s disease with an interleukin-1alpha gene polymorphism. Ann Neurol 47:361–365

    Google Scholar 

  • Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM (2004) Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 26:61–69

    Article  PubMed  Google Scholar 

  • Hunot S and Hirsch EC (2003) Neuroinflammatory processes in Parkinson’s disease. Ann Neurol 53(suppl 3):S49–S58

    Google Scholar 

  • King PH, Redden D, Palmgren JS, Nabors LB, Lennon VA (1999) Hu antigen specificities of ANNA-I autoantibodies in paraneoplastic neurological disease. J Autoimmun 13:435–443

    Google Scholar 

  • Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608

    Article  CAS  PubMed  Google Scholar 

  • Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108

    CAS  PubMed  Google Scholar 

  • Laird NM, Horvath S, Xu X (2000) Implementing a unified approach to family-based tests of association. Genet Epidemiol 19 (suppl 1):S36–S42

    Google Scholar 

  • Laliberte RE, Perregaux DG, Hoth LR, Rosner PJ, Jordan CK, Peese KM, Eggler JF, Dombroski MA, Geoghegan KF, Gabel CA (2003) Glutathione s-transferase omega 1–1 is a target of cytokine release inhibitory drugs and may be responsible for their effect on interleukin-1beta posttranslational processing. J Biol Chem 278:16567–16578

    Google Scholar 

  • Levine TD, Gao F, King PH,rews LG, Keene JD (1993) Hel-N1: an autoimmune RNA-binding protein with specificity for 3′ uridylate-rich untranslated regions of growth factor mRNAs. Mol Cell Biol 13:3494–3504

    Google Scholar 

  • Li YJ, Scott WK, Hedges DJ, Zhang F, Gaskell PC, Nance MA, Watts RL et al (2002) Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 70:985–993

    Google Scholar 

  • Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Hulette C, Scherzer CR et al (2004) Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet 13:573

    Google Scholar 

  • Ma WJ, Chung S, Furneaux H (1997) The Elav-like proteins bind to AU-rich elements and to the poly(A) tail of mRNA. Nucleic Acids Res 25:3564–3569

    Google Scholar 

  • Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 67:146–154

    Article  CAS  PubMed  Google Scholar 

  • Martin ER, Bass MP, Gilbert JR, Pericak-Vance MA, Hauser ER (2003) Genotype-based association test for general pedigrees: the genotype-PDT. Genet Epidemiol 25:203–213

    Article  CAS  PubMed  Google Scholar 

  • Monks SA and Kaplan NL (2000) Removing the sampling restrictions from family-based tests of association for a quantitative-trait locus. Am J Hum Genet 66:576–592

    Google Scholar 

  • Nabors LB, Gillespie GY, Harkins L, King PH (2001) HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3′ untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res 61:2154–2161

    Google Scholar 

  • Perrone-Bizzozero N and Bolognani F (2002) Role of HuD and other RNA-binding proteins in neural development and plasticity. J Neurosci Res 68:121–126

    Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  CAS  PubMed  Google Scholar 

  • Ringheim GE, Conant K (2004) Neurodegenerative disease and the neuroimmune axis (Alzheimer’s and Parkinson’s disease, viral infections). J Neuroimmunol 147:43–49

    Google Scholar 

  • Sakai K, Kitagawa Y, Hirose G (1999) Binding of neuronal ELAV-like proteins to the uridine-rich sequence in the 3’-untranslated region of tumor necrosis factor-alpha messenger RNA. FEBS Lett 446:157–162

    Google Scholar 

  • Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons K, Pahwa R et al (2001) Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA 286:2239–2244

    Google Scholar 

  • Sengupta S, Jang BC, Wu MT, Paik JH, Furneaux H, Hla T (2003) The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. J Biol Chem 278:25227–25233

    Google Scholar 

  • Sully G, Dean JL, Wait R, Rawlinson L, Santalucia T, Saklatvala J, Clark AR (2004) Structural and functional dissection of a conserved destabilizing element of cyclo-oxygenase-2 mRNA: evidence against the involvement of AUF-1 [AU-rich element/poly(U)-binding/degradation factor-1], AUF-2, tristetraprolin, HuR (Hu antigen R) or FBP1 (far-upstream-sequence-element-binding protein 1). Biochem J 377:629–639

    Google Scholar 

  • Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E, Henson J, Posner JB, and Furneaux HM (1991) HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal. Cell 67:325–333

    Article  CAS  PubMed  Google Scholar 

  • Weiner HL, Selkoe DJ (2002) Inflammation and therapeutic vaccination in CNS diseases. Nature 420:879–884

    Google Scholar 

  • Yao KM, Samson ML, Reeves R, White K (1993) Gene elav of Drosophila melanogaster: a prototype for neuronal-specific RNA binding protein gene family that is conserved in flies and humans. J Neurobiol 24:723–739

    Google Scholar 

  • Zaykin D, Zhivotovsky L, Weir BS (1995) Exact tests for association between alleles at arbitrary numbers of loci. Genetica 96:169–178

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to all of the families whose participation made this project possible. We thank the members of the PD Genetics collaboration Martha A. Nance, Ray L. Watts, Jean P. Hubble, William C. Koller, Kelly Lyons, Rajesh Pahwa, Matthew B. Stern, Amy Colcher, Bradley C. Hiner, Joseph Jankovic, William G. Ondo, Fred H. Allen Jr., Christopher G. Goetz, Gary W. Small, Donna Masterman, Frank Mastaglia and Jonathan L. Haines who contributed families to the study. We would also like to thank Dr. Eden Martin, Dr. Bill Scott, Dr. Jack Keen, and Dr. Peter King for helpful discussions on this work. This research was supported by the NIH/NINDS R01 NS311530-10 and P50-NS-039764 grants.

Author information

Authors and Affiliations

  1. Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, Box 3445, 27710, NC, USA

    Maher A. Noureddine, Xue-Jun Qin, Sofia A. Oliveira, Tara J. Skelly, Joelle van der Walt, Michael A. Hauser, Margaret A. Pericak-Vance, Jeffery M. Vance & Yi-Ju Li

Authors
  1. Maher A. Noureddine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xue-Jun Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sofia A. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tara J. Skelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joelle van der Walt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael A. Hauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Margaret A. Pericak-Vance
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jeffery M. Vance
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yi-Ju Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi-Ju Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Noureddine, M.A., Qin, XJ., Oliveira, S.A. et al. Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease. Hum Genet 117, 27–33 (2005). https://doi.org/10.1007/s00439-005-1259-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-005-1259-2

Keywords

Search

Navigation